ABSTRACT Bone is a dynamic organ that is known to adjust in mass, material and architectural properties with respect to the load environment. The progressive decline in muscle mass, strength/performance (sarcopenia) and bone loss (osteopenia/osteoporosis) that occurs with aging suggests a functional coupling between the diseases. As the osteocyte is thought to be the mechanosensory cell in bone, an age-related reduction in its ability to respond to load would have significant consequences on bone mass. We have shown that the Wnt/?-catenin signaling pathway is a critical component of bone responsiveness to mechanical loading and is rapidly activated in osteocytes following the in vivo application of load. Our Preliminary Data demonstrate an important role of estrogen in the response of osteocytes to load. We also found that ex vivo contracted EDL muscles from 6 month old C57BL/6 mice release a factor that enhances activation of ?-catenin in osteocytes. This enhancement effect is lost in 22 month old muscles. Using our recently developed ?-catenin signaling osteocyte reporter cell line (TOPflash MLO-Y4), we found that C2C12 myotube conditioned media (MTCM) synergistically enhances Wnt3a induced ?-catenin signaling and this is partially regulated by mTOR. This project will test the hypothesis that loss of estrogen mediated signaling with aging impairs crosstalk signaling between bone and muscle. To test this hypothesis we propose two specific aims. In Aim 1 we will determine if loss of ER mediated signaling in osteocytes alters critical bone-muscle crosstalk signaling pathways. In Aim 2 we will determine if loss of ER mediated signaling in muscle will induce changes in muscle and bone function and properties with aging and if exercise will protect against these changes in young mice. These aims will be accomplished using young (5-6 mo old), mature (12 mo) and aged (22 mo) mouse models with targeted deletion of estrogen receptors in muscle and bone. In vitro studies using bone and muscle cell model systems and primary cells will be used to dissect the molecular basis for the changes we observe in vivo. The information obtained from these studies is foundational for our understanding of how bone and muscle age, the potential mitigating effects of exercise and the possible molecular linkage between osteoporosis and sarcopenia.